Angiogenesis is defined as the growth of blood vessels from preexisting microvasculature. Therapeutic angiogenesis seeks to employ this phenomenon to treat patients with inadequate tissue perfusion by inducing neovascular growth. The goals of this project are: to develop anatomically-, biophysically-, and physiologically-detailed integrative multi-scale computational models of angiogenesis in normal and diseased skeletal muscle; to use highly synergistic and interactive computational and experimental approaches to understand physiologic and pathologic adaptations in mouse and human muscle; and to design improved and novel human therapeutics. Specifically, the experimentally-validated computational models will be used to understand, design and optimize therapies for human peripheral arterial obstructive disease (PAOD), a major cause of amputation and death. Currently there are no medical therapies available for PAOD that have the ability to increase perfusion and correct the principal abnormality of impaired blood flow. The vascular endothelial growth factor (VEGF) family of ligands and receptors will serve as the core focus of this project. To synthesize computational and experimental approaches, a collaboration has been established between computational biologists/bioengineers from Johns Hopkins University and basic/translational scientists from Duke University School of Medicine. Experimental data will be obtained from tissues of the normal and diabetic mouse and human with and without PAOD and the results will be utilized in multi-scale computational models, spanning from the molecule, to the tissue, to the organism level. The iteration of computational and experimental approaches will permit unparalleled investigation in the highly significant field of angiogenesis. This inter-disciplinary approach will have an immediate impact on fields that range from biology, to cell physiology, through human health and disease. The relevance of the research to public health would go beyond the applications to peripheral arterial obstructive disease, since over 70 diseases are presently identified as angiogenesis-dependent, including ischemic heart disease, cancer, macular degeneration, rheumatoid arthritis, obesity, and neurodegenerative diseases. [unreadable] [unreadable] [unreadable]